Novel process for preparation of nebivolol intermediates

ABSTRACT

The present invention relates to a process for separation of desired diastereomeric pair from a mixture of diastereomeric pairs thereby obtaining nebivolol intermediates. Thus, the mixture of (+)-[1S*(R*)]-6-fluoro-3,4-di-hydro-α-[[(phenylmethyl)amino]methyl]-2H-1-benzopyran-2-methanol, (+)-[1S*(S*)]-6-fluoro-3,4-dihydro-2-oxi -ranyl-2H-1-benzopyran and ethanol is heated to reflux temperature and stirred for 8 hours at the same temperature to obtain (±)-[2R*[1S*,5S*(S*)]]+[2R*[1S*,5R*(R*)]]-α,α′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran ran-2-methanol]. Then the reaction mass is cooled to 10° C., the pH is adjusted to 2 with HCl gas and stirred for 45 minutes at 25° C. to 30° C. Then the separated solid is filtered and dried to give (+)-[2R*[1S*,5S*(S*)]]-α,α′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] hydrochloride salt, which can be converted into nebivolol.

FIELD OF THE INVENTION

The present invention relates to a process for separation of desireddiastereomeric pair from a mixture of diastereomeric pairs therebyobtaining nebivolol intermediates.

BACKGROUND OF THE INVENTION

EP Patent No. 0145067 disclosed 2,2′-iminobisethanol derivatives. Thecompounds are antihypertensive agents. Among them nebivolol, chemically(+)-[2R*[1S*,5S*(S*)]]-α,α^(l)-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]is the most important antihypertensive agent. Nebivolol is representedby the following structure:

The above structure has four stereogenic centers, which are indicatedwith No. 1, 2, 3 and 4. Nebivolol is a mixture of equal amounts of 2enantiomers having respectively the SRRR- and the RSSS-configuration.

Processes for preparations of nebivolol and related compounds weredescribed in EP Patent No. 0145067 and EP Patent No. 0334429. Accordingto the processes described in these patents, chromatographic separationsare required for the separation of diastereomeric pairs at theintermediate stage or at the final stage. The chromatographicseparations involve additional operations, additional expensive setupadding to the cost of production. U.S. Pat. No. 5,759,580 described theseparation of (+)-[2R*[1 S*.5S*(S*)]]-α,α′-[Iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]hydrochloride (nebivolol hydrochloride) from the mixture of (+)-[2R*[1S*, 5S*(S*)]]+[2R*[1S*,5R*(R*)]]-α,α^(l)[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol].The yield of the nebivolol hydrochloride is extremely low (6.6%).

We have discovered that when N-protected compound of formula:

wherein -Prot is a protecting group, is converted into a salt of it, thesalts can be subjected to fractional crystallization of the desireddiastereomeric pair from the mixture of diastereomeric pairs. Theseparation of the diastereomers of these N-protected compounds bycrystallization is not disclosed in the prior art. The separateddiastereomeric pair is a useful intermediate for the preparation ofnebivolol.

Fractional crystallization also allows the purification of theN-protected compounds from the reaction mass, thereby avoiding multiplepurifications of crude nebivolol.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel process for preparing acidadditional salts of compounds of formula I:

wherein

wherein

X each independently is halo, nitro or C₁-C₃ alkyl and n is 0-5; whichcomprises:a) treating a mixture containing racemic diastereomers of a compound offormula II:

wherein P is as defined in formula I;with a suitable acid to form the corresponding acid addition salt;b) subjecting the acid addition salt obtained in step (a) to thefractional crystallization from an alcoholic solvent, ketonic solvent,acetonitrile, dimethylformamide, dimethylsulfoxide and tetrahydrofuranor a mixture thereof to obtain the diastereomeric pair of compounds offormula I.

Stereochemical description describing the configurations at chiralcenters used here is in the order (1,2,3 and 4) mentioned in thestructure. Thus, for example, the stereochemical description R*S*S*S*shown in the formula I refers to R* configuration at the carbon ‘1’, S*configuration at 2 and so on and R*S*S*S* has the meaning shown below.

Alcoholic solvents are selected from the group consisting of C₁ toC₅-alcohols. Preferable alcoholic solvents are methanol, ethanol,propanol and isopropyl alcohol.

Ketonic solvents are selected from the group C₃ to C₈-ketones.Preferable ketonic solvents are acetone, methyl isobutyl ketone andmethyl tert-butyl ketone.

The acid addition salts are prepared by treating the mixture containingcompounds of formula II with the corresponding acids in a solvent byconventional means. The suitable acids are inorganic acids, for example,hydrogen halides, nitric acid, phosphoric acid; and organic acids suchas carboxylic acids, sulfonic acids. The examples for carboxylic acidsthat can be mentioned are acetic acid, propanoic acid, formic acid,hydroxyacetic acid, 2-hydroxy propanoic acid, 2-oxopropanoic acid,propanedioic acid, butanedioic acid, (Z)-2-butenedioic acid,(E)-2-butenedioic acid, 2-hydroxy butanedioic acid. The examples forsulfonic acids that can be mentioned are methane sulfonic acid, toluenesulfonic acid and benzene sulfonic acid.

The step (a) is preferably carried out in an organic solvent. Theselection of the solvent is not critical. The solvents may be selectedfrom the group consisting of c-i to C₅ -alcohols, C₃ to C₈-ketones, C₂to C₈-esters, acetonitrile, tetrahydrofuran, dimethylformamide,dimethylsulfoxide, dioxane, aromatic hydrocarbons, C₁ to C₅-halogenatedhydrocarbons and C₂ to C₈-ethers and a mixture thereof. Preferablealcoholic solvents are methanol, ethanol, propanol and isopropylalcohol; preferable ketonic solvents are acetone, methyl ethyl ketone,methyl isobutyl ketone, methyl tert-butyl ketone and diethyl ketone;preferable ester solvents are ethyl acetate, methyl acetate, isopropylacetate, tert-butyl methyl acetate and ethyl formate; preferablearomatic hydrocarbon solvents are benzene, toluene and xylene;preferable halogenated hydrocarbon solvents are methylene chloride,chloroform, carbontetrachloride and ethylene dichloride; and preferableether solvents are tert-butyl methyl ether and diethyl ether. Mostpreferable solvents are methanol, ethanol, propanol, isopropyl alcohol,acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butylketone, diethyl ketone, acetonitrile, dimethylformamide,dimethylsulfoxide and tetrahydrofuran.

Preferably, fractional crystallization may be carried out in essentiallyanhydrous conditions. Maintenance of anhydrous conditions duringcrystallization is not essential but is to avoid the incompletecrystallization of some acid addition salts.

Crystallization may be carried out by commonly known methods such ascooling, addition of an anti-solvent, seeding and partial removal of thesolvent or a combination thereof. The fractional crystallization maypreferably be carried out at about 0° C. to 45° C. and more preferablyat about 0° C. to 35° C.

The acid addition salts of formulas I and II are novel and also form thepart of the invention.

The preferred acid addition salts of formula I prepared according to thepresent invention are hydrogen halides, hydrogen sulfates, sulfates andsulfonic acid salts.

More preferred acid addition salts of formula I are hydrogen halidessuch as hydrogen chloride, hydrogen iodide and hydrogen bromide, stillmore preferred salt being hydrogen chloride salt.

Step (a) and (b) can be performed in the same solvent or differentsolvent. Even though the step (a) and (b) can be performed in differentsolvents, it is preferred to carry out the salt formation step andfractional crystallization in the same solvent in order to simplify theprocess.

Acid addition salts can also be prepared from the reaction mass obtainedas a part of the synthesis of the compounds of formula II.

The crystalline acid addition salts of the compound of formulas 1 & IIare novel.

The more preferred acid addition salts of compound of formula I preparedaccording to the present invention are hydrogen halide addition salts offormula III:

Still more preferred hydrogen halide addition salt of formula III ishydrogen chloride salt.

The process described above may also be used as a purification methodfor the removal of the undesired diastereomeric pair from the desireddiastereomeric pair by basifying the acid addition salt of compound offormula I contaminated with undesired diastereomeric pair and thenfollowing the process steps (a) and (b) described above. Thepurification can be performed till the desired diastereomeric puritylevel is attained.

The compounds of formula II may be obtained by the methods known in theart. Thus, for example, the compounds of formula II are obtained by theprocess described in EP Patent No. 0145067 and EP Patent No. 0334429.The patents EP Patent No. 0145067 and EP Patent No. 0334429 areincorporated herein by reference in their entirety.

The acid addition salts of formula I are intermediates for preparingnebivolol and pharmaceutical acceptable salts thereof and can beconverted into nebivolol by basifying with a base, removing theprotecting group ¹P′ by the processes known in the art and optionallyconverting nebivolol into a pharmaceutically acceptable salt. Thepharmaceutically acceptable salts were described in U.S. Pat. No.5,759,580 and incorporated herein by reference. The selection of thebase is not critical but may be selected from hydroxides, carbonates andbicarbonates of alkaline metals; ammonia and amines. The amine base maybe primary amine such as methylamine or ethylamine; secondary amine suchas diethylamine or dimethylamine; and tert-amine such as triethylamine,trimethylamine or dimethylaminopyridine. The basification may be carriedout in water or in an organic solvent or a mixture thereof. The organicsolvents used here may be selected from the group consisting of C₁ toC₅-alcohols, C₃ to C₈-ketones, C₂ to C₈-esters, acetonitrile,tetrahydrofuran, dimsthylformamide, dimethylsulfoxide, dioxane, aromatichydrocarbons, C₁ to C₅-halogenated hydrocarbons and C₂ to C₈-ethers anda mixture thereof. Preferable alcoholic solvents are methanol, ethanol,propanol and isopropyl alcohol; preferable ketonic solvents are acetone,methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketoneand diethyl ketone; preferable ester solvents are ethyl acetate, methylacetate, isopropyl acetate, tert-butyl methyl acetate and ethyl formate;preferable aromatic hydrocarbon solvents are benzene, toluene andxylene; preferable halogenated hydrocarbon solvents are methylenechloride, chloroform, carbontetrachloride and ethylene dichloride; andpreferable ether solvents are tert-butyl methyl ether and diethyl ether.Most preferable organic solvents are methanol, ethanol, propanol,isopropyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone,methyl tert-butyl ketone, diethyl ketone, acetonitrile,dimethylformamide, dimethylsulfoxide and tetrahydrofuran. Thus, forexample, if P is benzyl then catalytic hydrogenation using hydrogenationcatalyst such as palladium or platinum on carbon may be used for thede-protection and if P is allyl, then reaction with an appropriate noblemetal compound such as PdCl₂ or Rh[P(C₆H₅)3]Cl may be carried out.

The hydrogenation is carried out in a solvent. The selection of thesolvent is not critical and may be selected from the group consisting ofc-i to C₅-alcohols, C₃ ^(′ to C) ₈-ketones, C₂ to C₈-esters,acetonitrile, tetrahydrofuran, dimethyiformamide, dimethylsulfoxide,dioxane, aromatic hydrocarbons, C₁ to C₅-halogenated hydrocarbons and C₂to C₈-ethers and a mixture thereof. Preferable alcoholic solvents aremethanol, ethanol, propanol and isopropyl alcohol; preferable ketonicsolvents are acetone, methyl ethyl ketone, methyl isobutyl ketone,methyl tert-butyl ketone and diethyl ketone; preferable ester solventsare ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methylacetate and ethyl formate; preferable aromatic hydrocarbon solvents arebenzene, toluene and xylene; preferable halogenated hydrocarbon solventsare methylene chloride, chloroform, carbontetrachloride and ethylenedichloride; and preferable ether solvents are tert-butyl methyl etherand diethyl ether. Most preferable organic solvents are methanol,ethanol, propanol, isopropyl alcohol, acetone, methyl ethyl ketone,methyl isobutyl ketone, methyl tert-butyl ketone, diethyl ketone,acetonitrile, dimethyiformamide, dimethylsulfoxide and tetrahydrofuran.

‘Essentially anhydrous condition” refers to the water content less than10%, preferably less than 5% and more preferably less than 2% of thetotal mass by weight.

In a preferred process (+)-[1S*(R*)]- (or (+)-[1S*(S*)])-6-fluoro-3,4-dihydro-α-[[(phenylmethyl)amino]methyl]-2H-1-benzopyran-2-methanolis reacted with (+)-[1S*(S*)]- (or(+)[1S*(R*)])-6-fluoro-3,4-dihydro-2-oxiranyl-2H-i-benzopyran in an C₁to C₅-alcohol or C₃ to C₈-ketone solvent to obtain(+)-[2R*[1S*,5S*(S*)]]+[2R*[1S*,5R*(R*)]]-α,α^(I)-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol], hydrogen halide,sulfate or hydrogen sulfate is added to the reaction mass,crystallization is performed at about 0° C. to 45° C., the separatedsolid is filtered to obtain the corresponding salt of(+)-[2R*[1S*,5S*(S*)]]-α,α′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol],the salt is basified in a solvent to obtain (+)-[2R*[1S*,5S*(S*)]]-a,a′-[phenylmethyliminobis(methylene)bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]free base and the free base is subjected to catalytic hydrogenation withhydrogen using palladium on carbon as catalyst.

The addition of hydrohalide may be performed by passing hydrogen halidegas, e.g., HCl (g) to the reaction mass or adding hydrogen halidedissolved in a solvent to the reaction mass.

Unless otherwise specified, the alkyl portion of the C₁ to C₅-alcohol,C₃ to C₈-ketone, C₂ to C₈-ester, Ci to C₅-halogenated hydrocarbon and C₂to C₈-ether used can be straight or branch, unsubstituted or substitutedwith for example alkoxy, halogen, nitro, cyano or hydroxy groups.

The invention will now be further described by the following examples,which are illustrative rather than limiting.

EXAMPLE 1

The solution of benzyl amine (14.89 gm) in ethanol (90 ml) is added to amixture of (+)-[1S*(R*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran(9 gm) and ethanol (90 ml) drop wise at reflux temperature for 15minutes. The temperature of the reaction mixture is raised to reflux andmaintained for 5 hours at reflux temperature. Then ethanol is distilledoff under vacuum at 50° C. To this residue diisopropyl ether (50 ml)added and stirred for 30 minutes at 0-5° C. Then the separated solid isfiltered, washed with chilled diisopropylether and dried to give 8.5 gmof(+)-[1S*(R*)]-6-fluoro-3,4-dihydro-α-[[(phenylmethyl)amino]methyl]-2H-1-benzopyran-2-methanol(HPLC purity: 97%).

EXAMPLE 2

The mixture of (+)-[1S*(R*)]-6-fluoro-3,4-dihydro-α-[[(phenylmethyl)amino]methyl]-2H-1-benzopyran-2-methanol (100 gm, obtained in example1), (±)-[1S*(S*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (90gm) and ethanol (2000 ml) is heated to reflux temperature and stirredfor 8 hours at the same temperature to obtain (+)-[2R*[1S*,5S*(S*)]]+[2R*[1S*,5R*(R*)]]-α,oc′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]((±)-[2R*[1S*, 5S*(S*)]] to (+)-[2R*[1 S*,5R*(R*)]] ratio is 1: 1.1).Then the reaction mass is cooled to 10° C., the pH is adjusted to 2 withHCl gas and stirred for 45 minutes at 25° C. to 30° C. Then theseparated solid is filtered and dried to give 80.7 gm of (+)-[2R*[1 S*,5S*(S*)]]-α,α′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]hydrochloride salt (HPLC purity 99.0%; (±)-[2R*[1 S*, 5S*(S*)]] to(+)-[2R*[1S*,5R*(R*)]] ratio is 99.4:0.6).

EXAMPLE 3

The mixture of 10% NaHCO₃ solution (800 ml) and (+)-[2R*[1S*,5S*(S*)]]-α,α′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]hydrochloride salt (80.7 gm) obtained above is stirred for 15 minutesand then extracted twice with ethyl acetate (1600 ml). Then the organiclayer is washed with water (800 ml) and 20% sodium chloride solution(400 ml) and then distilled off the solvent to give 38.4 gm of(+)-[2R*[1 S*, 5S*(S*)]]-α,α′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]residue.

The mixture of (+)-[2R*[1S*, 5S*(S*)]]-α,α′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] residue(38.4 gm, obtained above, 10% palladium on charcoal (10 gm) and ethanol(1300 ml) is taken into a hydrogenation flask and subjected tohydrogenation under a hydrogen gas pressure<of 2.5 kg/cm²for 3 hours.Then the reaction mixture is filtered on hi-flo and washed with ethanol.The solvent is distilled off, acetonitrile (200 ml) is added and stirredfor 10 minutes. Then the separated solid is filtered and washed withacetonitrile to give 10 gm of (+)-[2R*[1 SV5S*(S*)]]-α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol](Nebivolol) (HPLC purity: 99.3%).

EXAMPLE 4

Nebivolol (10 gm) obtained in example 3 is dissolved in the mixture ofmethylene dichloride (150 ml) and ethanol (100 ml) at 45° C. and thencooled to 10° C. Then pH of the solution is adjusted to 2 with HCl gas,stirred for 10 minutes and distilled the solvent. Then the solid isfiltered and washed with acetone to give 7 gm of Nebivolol hydrochloridesalt (HPLC purity: 99.8%).

1. A process for preparing acid additional salts of compounds of formulaI:

wherein

wherein X each independently is halo, nitro or C₁-C₃ alkyl and n is 0-5;which comprises: a) treating a mixture containing racemic diastereomersof a compound of formula II:

wherein P is as defined in formula I; with a suitable acid to form thecorresponding acid addition salt; b) subjecting the acid addition saltobtained in step (a) to the fractional crystallization from an alcoholicsolvent, ketonic solvent, acetonitrile, dimethylformamide,dimethylsulfoxide and tetrahydrofuran or mixture there of to obtain thediastereomeric pair of compound of formula I.
 2. The process accordingto claim 1, wherein the alcoholic solvent is selected from the groupconsisting of C₁ to C₅-alcohols.
 3. The process according to claim 2,wherein the alcoholic solvent is selected from methanol, ethanol,propanol and isopropyl alcohol.
 4. The process according to claim 3,wherein the alcoholic solvent is ethanol.
 5. The process according toclaim 1, wherein the ketonic solvent is selected from the groupconsisting of C₃ to C₈-ketones.
 6. The process according to claim 5,wherein the ketonic solvent is selected from acetone, methyl isobutylketone and methyl tert-butyl ketone.
 7. The process according to claim6, wherein the ketonic solvent is acetone.
 8. The process according toclaim 1, wherein the acid addition salt is prepared by treating themixture containing compounds of formula II with the corresponding acidin a solvent.
 9. The process according to claim 8, wherein the acid isinorganic acid or an organic acid.
 10. The process according to claim 9,wherein the inorganic acid is a hydrogen halide, nitric acid orphosphoric acid.
 11. The process according to claim 10, wherein thehydrogen halide is hydrogen chloride.
 12. The process according to claim9, wherein the organic acid is a carboxylic acid or a sulfonic acid. 13.The process according to claim 12, wherein the carboxylic acid isselected from acetic acid, propanoic acid, formic acid, hydroxyaceticacid, 2-hydroxy propanoic acid, 2-oxopropanoic acid, propane dioic acid,butanedioic acid, (Z)-2-butenedioic acid, (E)-2-butenedioic acid and2-hydroxy butanedioic acid.
 14. The process according to claim 12,wherein the sulfonic acid is selected from methane sulfonic acid,toluene sulfonic acid and benzene sulfonic acid.
 15. The processaccording to claim 8, wherein the solvent is an organic solvent.
 16. Theprocess according to claim 15, wherein the organic solvent is selectedfrom the group consisting of C₁ to C₅-alcohols, C₃ to C₈-ketones, C₂ toC₈-esters, acetonitrile, tetrahydrofuran, dimethylformamide,dimethylsulfoxide, dioxane, aromatic hydrocarbons, C₁ to C₅-halogenatedhydrocarbons and C₂ to C₈-ethers and mixtures thereof.
 17. The processaccording to claim 16, wherein the alcoholic solvents are methanol,ethanol, propanol and isopropyl alcohol; ketonic solvents are acetone,methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketoneand diethyl ketone; ester solvents are ethyl acetate, methyl acetate,isopropyl acetate, tert-butyl methyl acetate and ethyl formate; thearomatic hydrocarbon solvents are benzene, toluene and xylene; thehalogenated hydrocarbon solvents are methylene chloride, chloroform,carbontetrachloride and ethylene dichloride; and the ether solvents aretert-butyl methyl ether and diethyl ether.
 18. The process according toclaim 16, wherein the organic solvent is selected from methanol,ethanol, propanol, isopropyl alcohol, acetone, methyl ethyl ketone,methyl isobutyl ketone, methyl tert-butyl ketone, diethyl ketone,acetonitrile, dimethylformamide, dimethylsulfoxide and tetrahydrofuran.19. The process according to claim 18, wherein the organic solvent ismethanol, ethanol or acetone.
 20. The process according to claim 1,wherein the fractional crystallization is carried out in anhydrouscondition.
 21. The process according to claims 1, wherein thecrystallization is carried out by cooling, addition of anti-solvents,seeding or partial removal of the solvents or combinations thereof. 22.The process according to claim 21, wherein the crystallization iscarried out at about 0° C. to 45° C.
 23. The process according to claim22, wherein the crystallization is carried out at about 0° C. to 35° C.24. The process according to claim 1, wherein the steps (a) and (b) areperformed in the same solvent or different solvent.
 25. The processaccording to claim 24, wherein the steps (a) and (b) are performed indifferent solvents.
 26. The process according to claim 1, wherein theacid addition salts of formula I are prepared from a reaction massobtained as a part of the synthesis of the compounds of formula II. 27.The process according to claims 1, wherein the acid addition salts ofcompound of formula I prepared according to the present invention arehydrogen halide addition salts of formula III:


28. The process according to claim 27, wherein the hydrogen halide saltof formula III is hydrogen chloride salt.
 29. A process for thepreparation of nebivolol or a pharmaceutically acceptable salt thereof,which comprises the steps of: a) reacting6-fluoro-3,4-dihydro-α-[[(phenylmethyl)amino]methyl]-2H-1-benzopyran-2-methanolwith 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran in an C₁ toC₅-alcohol or C₃ to C₈-ketone solvent to produce(+)-[2R*[1S*,5S*(S*)]]+[2R*[1S*,5R*(R*)]]-α,α′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol];b) treating(+)-[2R*[1S*,5S*(S*)]]+[2R*[1S*,5R*(R*)]]-α,α′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]produced in step (a) with hydrogen halide, sulfate or hydrogen sulfate;subjecting to fractional crystallization at about 0° C. to 45° C. andfiltering the separated solid to produce corresponding salt of(+)-[2R*[1S*,5S*(S*)]]-α,α′-[phenylmethyliminobis (methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran -2-methanol]; c) basifying thesalt of (+)-[2R*[1S*,5S*(S*)]]-α,α′-[phenylmethylimino bis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] produced in step(b)in a solvent to produce (+)-[2R*[1S*,5S*(S*)]]-α,α′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] free base; and d)subjecting(+)-[2R*[1S*,5S*(S*)]]-α,α′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] free base to catalytichydrogenation with hydrogen using palladium on carbon as a catalyst toobtain nebivolol and optionally converting to the pharmaceuticallyacceptable salt.
 30. The process according to claim 29, wherein thealcoholic solvent is selected from the group consisting of C₁ toC₅-alcohols.
 31. The process according to claim 30, wherein thealcoholic solvent is selected from methanol, ethanol, propanol andisopropyl alcohol.
 32. The process according to claim 31, wherein thealcoholic solvent is ethanol.
 33. The process according to claim 29,wherein the ketonic solvent is selected from the group consisting of C₃to C₈-ketones.
 34. The process according to claim 33, wherein theketonic solvent is selected from acetone, methyl isobutyl ketone andmethyl tert-butyl ketone.
 35. The process according to claim 34, whereinthe ketonic solvent is acetone.
 36. The process according to claim 29,wherein the hydrogen halide is hydrogen chloride.
 37. The processaccording to claim 36, wherein the treatment in step (b) is carried outby passing hydrogen chloride gas to the mass containing (+) -[2R*[1S*,5S*(S*)]]+[2R*[1S*,5R*(R*)]]-α,α′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol](or) by adding a solution of hydrogen chloride in a solvent to the masscontaining (+)-[2R*[1S*,5S*(S*)]]+[2R*[1S*,5R*(R*)]]-α,α′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol].
 38. Acidaddition salts of formulas I and II:

wherein

wherein X each independently is halo, nitro or C₁-C₃ alkyl and n is 0-5;

wherein P is as defined in formula I.
 39. The acid addition salts ofclaim 38, wherein the said salts are hydrogen halides, hydrogensulfates, sulfates and sulfonic acid salts.
 40. The acid addition saltsof claim 39, wherein the said salts are hydrogen halides.
 41. The acidaddition salts of claim 40, wherein the said salts are hydrogenchloride, hydrogen iodide and hydrogen bromide.
 42. The acid additionsalts of claim 41, wherein the said salt is hydrogen chloride.
 43. Theprocess according to claim 20, wherein the crystallization is carriedout by cooling, addition of anti-solvents, seeding or partial removal ofthe solvents or combination thereof.
 44. The process according to claim26, wherein the acid addition salts of compound of formula I preparedaccording to the present invention are hydrogen halide addition salts offormula III: